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1.
Cell Biol Int ; 44(10): 2053-2064, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32584509

RESUMO

Nucleotide-binding domain, leucine-rich repeat family with a caspase activation and recruitment domain 3 (NLRC3) participates in both immunity and cancer. The aim of this study was to determine the role of NLRC3 in human hepatocellular carcinoma (HCC) and the underlying mechanisms. We collected human liver tissues from nonalcoholic steatohepatitis (NASH), HCC, and adjacent normal tissues to characterize the pattern of NLRC3 expression by real-time quantitative polymerase chain reaction and immunohistochemistry. Then, we used the HCC cell line, HuH-7, transfected with small interfering RNA to silence the NLRC3 expression. 5-Ethynyl-2'-deoxyuridine assay, scratch assay, and transwell invasion assay were used for assessing proliferation, migration, and invasion, respectively. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were conducted to assess cell apoptosis. The expression of NLRC3 was reduced in human HCC tissues, compared with normal liver and nonalcoholic steatohepatitis tissues. After knocking down of NLRC3, the proliferation, migration, and invasion were increased in HuH-7 cells. And flow cytometry and TUNEL assay showed that HuH-7 cell apoptosis was suppressed after NLRC3 knockdown. As for the underlying mechanisms, knockdown of NLRC3 in HuH-7 cells was associated with the activation of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway under interleukin-6 (IL-6) stimulation. NLRC3 expression was downregulated in human HCC tissues. NLRC3 silencing in HuH-7 cells can promote the proliferation, migration, and invasion of hepatocellular carcinoma cells. JAK2/STAT3 pathway activation induced by IL-6 may be the underlying mechanism for HCC when NLRC3 expression is silenced. And the invasion of HuH-7 cells was partially suppressed by the STAT3 specific inhibitor (cryptotanshinone). Therefore, NLRC3 may play a significant role in HCC and might be a therapeutic target for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Neoplasias Hepáticas , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Células THP-1
2.
FASEB J ; 32(2): 1070-1084, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29070585

RESUMO

NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has important roles in inflammation and innate immunity. NLRC5 was highly expressed in kidney from streptozotocin-induced diabetic mice, db/ db mice and patients with diabetes. Based on that evidence, the present study was designed to explore the roles of NLRC5 in the progression of diabetic nephropathy (DN). We examined kidney injury, including inflammation and fibrosis in Nlrc5 gene knockout ( Nlrc5-/-) and wild-type (WT) diabetic mice. We found that Nlrc5-/- mice developed less-severe diabetic kidney injury compared with WT mice, exhibiting lower albuminuria, less fibronectin and collagen IV expression, and reduced macrophage infiltration but greater levels of podocin and nephrin in the diabetic kidney. The underlying mechanisms were further investigated in vitro with peritoneal macrophages and mesangial cells treated with high glucose. Reduced proinflammatory effect was observed in peritoneal macrophages from Nlrc5-/- mice, associated with NF-κB pathway suppression. Knocking down of NLRC5 in mesangial cells in high-glucose conditions was also associated with reduced NF-κB and TGF-ß/Smad signaling. Taken together, NLRC5 promotes inflammation and fibrosis during DN progression partly through the effects on NF-κB and TGF-ß/Smad pathways. NLRC5 may, therefore, be a promising therapeutic target for DN treatment.-Luan, P., Zhuang, J., Zou, J., Li, H., Shuai, P., Xu, X., Zhao, Y., Kou, W., Ji, S., Peng, A., Xu, Y., Su, Q., Jian, W., Peng, W. NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Células Mesangiais/metabolismo , Transdução de Sinais , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Células Mesangiais/patologia , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
3.
JMIR Mhealth Uhealth ; 12: e48675, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38297510

RESUMO

Background: With the increasing prevalence of obesity, weight loss has become a critical issue in China. Self-managed weight loss through a mobile health (mHealth) app may be a prospective method. However, its practicability in different economic regions of China is unknown. Objective: This study aims to evaluate the effectiveness of self-managed weight loss through an mHealth app among individuals with obesity in different economic regions of China and to demonstrate the feasibility of online self-management for weight loss. Methods: A total of 165,635 Chinese adults who signed up for the mHealth app were included to analyze the body composition characteristics of individuals from different economic regions by χ2 analyses. Furthermore, 2 types of participants with obesity using mHealth monitoring, including 74,611 participants with a BMI ≥24.0 kg/m2 and 22,903 participants with a normal BMI but an excessive percentage of body fat (PBF), were followed for 6 months to explore the weight loss and fat loss effects in different economic regions of China and to find independent predictors associated with weight loss success by 2-tailed Student t test and multivariable logistic regression analysis. Results: There were 32,129 users from low-income regions and 133,506 users from high-income regions. The proportion of users with obesity in low-income regions was higher than in high-income regions, both based on BMI (15,378/32,129, 47.9% vs 59,233/133,506, 44.4%; P<.001) and PBF classification (19,146/32,129, 59.6% vs 72,033/133,506, 54%; P<.001). Follow-up analyses showed that the weight loss effect among participants with overweight or obesity in low-income regions was greater than in high-income regions (mean -4.93, SD 6.41 vs mean -4.71, SD 6.14 kg; P<.001), while there was no significant difference in fat loss (mean -2.06%, SD 3.14% vs mean -2.04%, SD 3.19%; P=.54). In the population with normal-weight obesity, the weight loss (mean -2.42, SD 4.07 vs mean -2.23, SD 4.21 kg; P=.004) and fat loss effects (mean -1.43%, SD 2.73% vs mean -1.27%, SD 2.63%; P<.001) were stronger in high-income regions than in low-income regions. In addition, multivariable logistic regression analyses showed that age, baseline PBF, skeletal muscle rate, and measurement frequency were related to weight loss, whereas gender and baseline body metabolic rate only showed a correlation with weight loss in the population in high-income regions. Conclusions: This study found a high proportion of mHealth app users with obesity in low-income regions. Individuals with overweight and obesity in different economic regions of China experienced significant weight loss and fat loss using an mHealth app. Moreover, individuals in high-income regions paid more attention to body fat and had better fat reduction effects. Therefore, promoting self-monitoring of weight and PBF through an mHealth app could be an important intervention that could be implemented across all regions of China.


Assuntos
Aplicativos Móveis , Telemedicina , Adulto , Humanos , Sobrepeso , Estudos de Coortes , Obesidade/epidemiologia , Obesidade/terapia , Redução de Peso , Telemedicina/métodos
4.
Cell Death Differ ; 31(2): 239-253, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38182899

RESUMO

Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC-MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.


Assuntos
Infarto do Miocárdio , Animais , Camundongos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Succinatos/metabolismo , Humanos
5.
Redox Biol ; 69: 103013, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38168657

RESUMO

Obesity is a complex metabolic disorder, manifesting as excessive accumulation of body fat. Ten-Eleven Translocation-2 (TET2) has garnered significant attention in the context of obesity due to its crucial role in epigenetic regulation and metabolic homeostasis. In this study, we aimed to investigate the effect of endothelial TET2 on obesity and explore the potential mechanism. We generated endothelial cell-specific TET2 deficiency mice and investigated endothelial TET2 using transcriptomic and epigenomic analyses. We determined the downregulation of endothelial TET2 in white adipose tissues. Furthermore, we identified that endothelial TET2 loss aggravated high-fat diet-induced obesity by inhibiting vascularization and thus suppressing white adipose tissue browning. Mechanistically, endothelial TET2 modulates obesity by engaging in endothelial fatty acid oxidation and angiocrine-mediated secretion of bone morphogenetic protein 4 (BMP4), in which nuclear factor-erythroid 2-related factor 2 (NRF2) serves as a key mediator. Our study reveals that endothelial TET2 regulates white adipose tissue browning by interacting with NRF2 to facilitate fatty acid oxidation and lipolysis in adipocytes.


Assuntos
Epigênese Genética , Fator 2 Relacionado a NF-E2 , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Tecido Adiposo Marrom/metabolismo , Obesidade/genética , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Ácidos Graxos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL
6.
Cell Biosci ; 13(1): 12, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658614

RESUMO

BACKGROUND: Ischemic diseases represent a major global health care burden. Angiogenesis is critical in recovery of blood flow and repair of injured tissue in ischemic diseases. Ten-eleven translocation protein 2 (TET2), a member of DNA demethylases, is involved in many pathological processes. However, the role of TET2 in angiogenesis is still unrevealed. METHODS: TET2 was screened out from three DNA demethylases involved in 5-hydroxylmethylcytosine (5-hmC) regulation, including TET1, TET2 and TET3. Knockdown by small interfering RNAs and overexpression by adenovirus were used to evaluate the role of TET2 on the function of endothelial cells. The blood flow recovery and density of capillary were analyzed in the endothelial cells-specific TET2-deficient mice. RNA sequencing was used to identify the TET2-mediated mechanisms under hypoxia. Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation-qPCR (ChIP-qPCR) and glucosylated hydroxymethyl-sensitive-qPCR (GluMS-qPCR) were further performed to reveal the interaction of TET2 and STAT3. RESULTS: TET2 was significantly downregulated in endothelial cells under hypoxia and led to a global decrease of 5-hmC level. TET2 knockdown aggravated the hypoxia-induced dysfunction of endothelial cells, while TET2 overexpression alleviated the hypoxia-induced dysfunction. Meanwhile, the deficiency of TET2 in endothelial cells impaired blood flow recovery and the density of capillary in the mouse model of hindlimb ischemia. Mechanistically, RNA sequencing indicated that the STAT3 signaling pathway was significantly inhibited by TET2 knockdown. Additionally, Co-IP, ChIP-qPCR and GluMS-qPCR further illustrated that STAT3 recruited and physically interacted with TET2 to activate STAT3 target genes. As expected, the effects of TET2 overexpression were completely suppressed by STAT3 silencing in vitro. CONCLUSIONS: Our study suggests that the deficiency of TET2 in endothelial cells impairs angiogenesis via suppression of the STAT3 signaling pathway. These findings give solid evidence for TET2 to be a therapeutic alternative for ischemic diseases.

7.
JACC Basic Transl Sci ; 8(5): 479-496, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37325412

RESUMO

Macrophages regulate inflammation and the process of tissue repair. Therefore, a better understanding of macrophages in the pathogenesis of heart failure is needed. In patients with hypertrophic cardiomyopathy, NLRC5 was significantly increased in circulating monocytes and cardiac macrophages. Myeloid-specific deletion of NLRC5 aggravated pressure overload-induced pathological cardiac remodeling and inflammation. Mechanistically, NLRC5 interacted with HSPA8 and suppressed NF-κB pathway in macrophages. The absence of NLRC5 in macrophages promoted the secretion of cytokines such as interleukin-6 (IL-6), which affected cardiomyocyte hypertrophy and cardiac fibroblast activation. Tocilizumab, an anti-IL-6 receptor antagonist, may be a novel therapeutic strategy for cardiac remodeling and chronic heart failure.

8.
Cardiovasc Diabetol ; 11: 65, 2012 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-22694757

RESUMO

BACKGROUND: Previous studies suggested that the RhoA/ROCK pathway may contribute to vascular complications in diabetes. The present study was designed to investigate whether ROCK inhibitor fasudil could prevent high glucose-induced monocyte-endothelial cells adhesion, and whether this was related to fasudil effects on vascular endothelial cell expression of chemotactic factors, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). METHODS: HUVECs were stimulated with high glucose (HG) or HG + fasudil in different concentration or different time. Monocyte-endothelial cell adhesion was determined using fluorescence-labeled monocytes. The mRNA and protein expression of VCAM-1 and MCP-1 were measured using real-time PCR and western blot. The protein levels of RhoA, ROCKI and p-MYPT were determined using western blot analysis. ELISA was employed to measure the expression of soluble VCAM-1 and MCP-1 in cell supernatants and human serum samples. RESULTS: Fasudil significantly suppressed HG-induced adhesion of THP-1 to HUVECs. Fasudil reduced Rho/ROCK activity (as indicated by lower p-MYPT/MYPT ratio), and prevented HG induced increases in VCAM-1 and MCP-1 mRNA and protein levels. Fasudil also decreased MCP-1 concentration in HUVEC supernatants, but increased sVCAM-1 shedding into the media. In human diabetic subjects, 2 weeks of fasudil treatment significantly decreased serum MCP-1 level from 27.9 ± 10.6 pg/ml to 13.8 ± 7.0 pg/ml (P < 0.05), while sVCAM-1 increased from 23.2 ± 7.5 ng/ml to 39.7 ± 5.6 ng/ml after fasudil treatment (P < 0.05). CONCLUSIONS: Treatment with the Rho/ROCK pathway inhibitor fasudil attenuated HG-induced monocyte-endothelial cell adhesion, possibly by reducing endothelial expression of VCAM-1 and MCP-1. These results suggest inhibition of Rho/ROCK signaling may have therapeutic potential in preventing diabetes associated vascular inflammation and atherogenesis.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Adesão Celular/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Idoso , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Western Blotting , Células Cultivadas , Quimiocina CCL2/sangue , Quimiocina CCL2/genética , Quimiotaxia de Leucócito/efeitos dos fármacos , China , Técnicas de Cocultura , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/enzimologia , Diabetes Mellitus/imunologia , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Inibidores de Proteínas Quinases/administração & dosagem , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Método Simples-Cego , Fatores de Tempo , Molécula 1 de Adesão de Célula Vascular/sangue , Molécula 1 de Adesão de Célula Vascular/genética , Quinases Associadas a rho/metabolismo
9.
Front Endocrinol (Lausanne) ; 13: 996814, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36440229

RESUMO

Background: Since 2020, longer stay-at-home time in response to the coronavirus disease 2019 (COVID-19) pandemic has changed the weight-related behaviors of Chinese population. Objectives: To explore the demographic and basic characteristics of body fat scale users and to investigate the changes in obesity-related body composition of overweight and obese users during COVID-19. Further, we analyzed the factors associated with successful weight loss and improved body composition changes in overweight and obese people. Methods: The study included 107,419 Chinese adults registered in the smart app connecting to the body fat scale in 2020 to describe the demographic characteristics of body fat scale users by Unpaired Student's t-test and Chi-Square test. Subsequently, overweight and obese participants with body mass index (BMI) of more than 24 kg/m2 were screened to investigate the independent factors associated with effective weight loss and improved body composition changes by multivariable logistic regression analyses. Results: During the pandemic, the number of body fat scale users increased markedly compared with pre-pandemic. Over half of the participants were women and with normal baseline BMI. Based on BMI classification, multivariable logistic regressions showed that age, gender, measurement frequency classification, baseline BMI, visceral adipose index and skeletal muscle rate were associated with weight loss and fat loss in the overweight and obese population, with the high-frequency measurement being the most important factor for effective weight and fat loss. In the population with normal BMI obesity, younger age was the most significant factor for effective fat loss. Conclusion: During the COVID-19 pandemic, participation in self-monitored weight loss increased markedly compared with pre-pandemic, and women accounted for the majority. We found that many overweight and obese participants achieved weight loss goals by smart body fat scales, and the effectiveness of weight and fat loss was greater in obese participants than in overweight participants, both based on BMI and PBF classification. In addition, promoting the usage of smart body fat scales could contribute to more effective weight and fat loss in the overweight and obese population based on BMI classification. However, in the population with normal BMI obesity, young subjects might be easier to successfully lose fat compared with the elder. Digital self-management by smart body fat scales could become a promising approach for the obese population with high BMI to lose weight and keep healthy.


Assuntos
COVID-19 , Autogestão , Adulto , Humanos , Feminino , Idoso , Masculino , Sobrepeso/epidemiologia , COVID-19/epidemiologia , Pandemias , Seguimentos , Redução de Peso/fisiologia , Obesidade/epidemiologia , Obesidade/terapia , Composição Corporal/fisiologia , Tecido Adiposo , China/epidemiologia
10.
Nat Commun ; 13(1): 7500, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36473863

RESUMO

Extracellular DNA traps (ETs) represent an immune response by which cells release essential materials like chromatin and granular proteins. Previous studies have demonstrated that the transdifferentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. This study seeks to investigate the interaction between CD68+ VSMCs and the formation of ETs and highlight its function in atherosclerosis. Here we show that ETs are inhibited, and atherosclerotic plaque formation is alleviated in male Myh11CrePad4flox/flox mice undergoing an adeno-associated-virus-8 (AAV8) mediating overexpression of proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) injection and being challenged with a high-fat diet. Obvious ETs generated from CD68+ VSMCs are inhibited by Cl-amidine and DNase I in vitro. By utilizing VSMCs-lineage tracing technology and single-cell RNA sequencing (scRNA-seq), we demonstrate that the ETs from CD68+ VSMCs influence the progress of atherosclerosis by regulating the direction of VSMCs' transdifferentiation through STING-SOCS1 or TLR4 signaling pathway.


Assuntos
Armadilhas Extracelulares , Masculino , Animais , Camundongos , Pró-Proteína Convertase 9 , Músculo Liso Vascular
11.
Int J Endocrinol ; 2021: 8820089, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33564304

RESUMO

BACKGROUND: Low-grade chronic inflammation in dysfunctional adipose tissue links obesity with insulin resistance through the activation of tissue-infiltrating immune cells. Numerous studies have reported on the pathogenesis of insulin-resistance. However, few studies focused on genes from genomic database. In this study, we would like to explore the correlation of genes and immune cells infiltration in adipose tissue via comprehensive bioinformatics analyses and experimental validation in mice and human adipose tissue. METHODS: Gene Expression Omnibus (GEO) datasets (GSE27951, GSE55200, and GSE26637) of insulin-resistant individuals or type 2 diabetes patients and normal controls were downloaded to get differently expressed genes (DEGs), and GO and KEGG pathway analyses were performed. Subsequently, we integrated DEGs from three datasets and constructed commonly expressed DEGs' PPI net-works across datasets. Center regulating module of DEGs and hub genes were screened through MCODE and cytoHubba in Cytoscape. Three most significant hub genes were further analyzed by GSEA analysis. Moreover, we verified the predicted hub genes by performing RT qPCR analysis in animals and human samples. Besides, the relative fraction of 22 immune cell types in adipose tissue was detected by using the deconvolution algorithm of CIBERSORT (Cell Type Identification by Estimating Relative Subsets of RNA Transcripts). Furthermore, based on the significantly changed types of immune cells, we performed correlation analysis between hub genes and immune cells. And, we performed immunohistochemistry and immunofluorescence analysis to verify that the hub genes were associated with adipose tissue macrophages (ATM). RESULTS: Thirty DEGs were commonly expressed across three datasets, most of which were upregulated. DEGs mainly participated in the process of multiple immune cells' infiltration. In protein-protein interaction network, we identified CSF1R, C1QC, and TYROBP as hub genes. GSEA analysis suggested high expression of the three hub genes was correlated with immune cells functional pathway's activation. Immune cell infiltration and correlation analysis revealed that there were significant positive correlations between TYROBP and M0 macrophages, CSF1R and M0 macrophages, Plasma cells, and CD8 T cells. Finally, hub genes were associated with ATMs infiltration by experimental verification. CONCLUSIONS: This article revealed that CSF1R, C1QC, and TYROBP were potential hub genes associated with immune cells' infiltration and the function of proinflammation, especially adipose tissue macrophages, in the progression of obesity-induced diabetes or insulin-resistance.

12.
Theranostics ; 11(9): 4483-4501, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754073

RESUMO

Angiogenesis is a critical step in repair of tissue injury. The pattern recognition receptors (PRRs) recognize pathogen and damage associated molecular patterns (DAMPs) during injury and achieve host defense directly. However, the role of NLR family CARD domain containing 5 (NLRC5), an important member of PPRs, beyond host defense in angiogenesis during tissue repair remains unknown. Methods:In vitro, western blot and real-time PCR (RT-PCR) were used to detect the expression of NLRC5 in endothelial cells (ECs). Immunofluorescence microscopy was used to reveal the subcellular location of NLRC5 in ECs. Cell proliferation, wound healing, tube formation assays of ECs were performed to study the role of NLRC5 in angiogenesis. By using Tie2Cre-NLRC5flox/flox mice and bone marrow transplantation studies, we defined an EC-specific role for NLRC5 in angiogenesis. Mechanistically, co-immunoprecipitation studies and RNA sequencing indicated that signal transducer and activator of transcription 3 (STAT3) was the target of NLRC5 in the nucleus. And Co-IP was used to verify the specific domain of NLRC5 binding with STAT3. ChIP assay determined the genes regulated by interaction of STAT3 and NLRC5. Results: Knockdown of NLRC5 in vitro or in vivo inhibited pathological angiogenesis, but had no effect on physiological angiogenesis. NLRC5 was also identified to bind to STAT3 in the nucleus required the integrated death-domain and nucleotide-binding domain (DD+NACHT domain) of NLRC5. And the interaction of STAT3 and NLRC5 could enhance the transcription of angiopoietin-2 (Ang2) and cyclin D1 (CCND1) to participate in angiogenesis. Conclusions: In the ischemic microenvironment, NLRC5 protein accumulates in the nucleus of ECs and enhances STAT3 transcriptional activity for angiogenesis. These findings establish NLRC5 as a novel modulator of VEGFA signaling, providing a new target for angiogenic therapy to foster tissue regeneration.


Assuntos
Células Endoteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neovascularização Patológica/metabolismo , Fator de Transcrição STAT3/metabolismo , Angiopoietina-2/metabolismo , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Ciclina D1/metabolismo , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Transdução de Sinais/fisiologia , Células THP-1 , Transcrição Gênica/fisiologia
13.
Mol Med Rep ; 22(6): 4890-4898, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33174610

RESUMO

Peripheral arterial disease (PAD) is the third leading cause of cardiovascular morbidity worldwide, after coronary artery disease and stroke. As endogenous regulators of gene expression, microRNAs (miRs) are implicated in the development and progression of various diseases, including types of cancer, autoimmune diseases and heart diseases. In the present study, the role of miR­124­3p in PAD was investigated. The reverse transcription­quantitative PCR results indicated that the expression levels of miR­124­3p were significantly increased in the ischemic tissue of the hindlimb ischemia (HLI) model and in hypoxic human umbilical vein endothelial cells compared with the corresponding control groups. Proliferation, wound healing and tube formation assays demonstrated the inhibition of miR­124­3p on angiogenesis in vitro and the HLI model indicated the same function of miR­124­3p in vivo. A dual­luciferase reporter revealed STAT3 as the target of miR­124­3p. The expression levels of miR­124­3p in human blood were negatively correlated with ankle­brachial index, which is an index for the evaluation of the severity of PAD. Collectively, the present study indicated that miR­124­3p was a critical regulator of angiogenesis in PAD, and a potential diagnostic, prognostic and therapeutic target for PAD.


Assuntos
MicroRNAs/genética , Doença Arterial Periférica/genética , Fator de Transcrição STAT3/metabolismo , Idoso , Indutores da Angiogênese/metabolismo , Animais , Hipóxia Celular/genética , China , Feminino , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Isquemia/genética , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Morfogênese , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , Doença Arterial Periférica/metabolismo , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia
14.
Ann Transl Med ; 8(7): 479, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32395523

RESUMO

BACKGROUND: Our previous study showed that visceral adipose tissue-derived serpin (vaspin) was an independent predictor of coronary artery disease (CAD). Further, plasma vaspin levels in patients with unstable angina pectoris were lower than those in patients with stable angina pectoris. In this study, we investigated the prognostic relevance of plasma vaspin levels in patients with CAD and non-CAD. METHODS: It was a retrospective observational study. A total of 197 patients with chest pain were enrolled, of which 88 patients with CAD and 109 patients with non-CAD were confirmed by angiography. Plasma vaspin levels and clinical parameters were measured at baseline. Incidence of major adverse cardiac event (MACE) was determined on follow-up. RESULTS: One hundred eighty-nine patients were successfully followed up for 5 years, of which 63 patients experienced MACEs. Patients with low vaspin levels (<0.385 ng/mL) experienced a higher incidence of MACE as compared to patients with high vaspin levels (>0.385 ng/mL) (42.55% vs. 24.21%, respectively; P=0.007). In both CAD and non-CAD groups, patients with high vaspin levels showed improvement in left ventricular ejection fraction. Kaplan Meier survival curves showed that patients with low vaspin levels had an obviously higher timing of incidence of MACE in the whole population (P=0.006) and in the non-CAD subgroup (P=0.009); however, the trend was not significant in the CAD subgroup. On multivariate analyses, plasma vaspin level was found to be an independent predictor of MACE, particularly in the non-CAD group. CONCLUSIONS: Plasma vaspin may be a useful biomarker for prediction of MACE in patients with chest pain.

15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 26(2): 161-4, 2009 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-19350507

RESUMO

OBJECTIVE: To study the genetic determination of fast plasma glucose (FPG) and correlation with its potential correlated traits, anthropometric measures and blood pressure. METHODS: Two hundred and eighteen Type 2 diabetes mellitus (T2DM) pedigrees composed of 1383 Chinese Han individuals residing in the East and South-East China were analyzed. Univariate variance decomposition analyses were used to estimate the narrow-sense heritability (h(2)) of FPG, anthropometric indices and blood pressure, and bivariate quantitative genetic analyses were used to estimate the genetic and environmental correlations between FPG and anthropometric measures or blood pressure. RESULTS: We found that FPG, blood pressure and all anthropometric indices except for waist to hip ratio were under significant genetic determination, and the h(2) was from 0.28 to 0.43. We did not find significant genetic and environmental correlation between FPG and anthropometric indices and blood pressure. CONCLUSION: The present study demonstrated that T2DM, obesity and hypertension were controlled by some genetic factors, and FPG shares little common genetic and environmental factors with obesity-related anthropometric indices and blood pressure in our Chinese sample population.


Assuntos
Antropometria , Glicemia/genética , Jejum/sangue , Fatores de Risco , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Pressão Sanguínea/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , China/etnologia , Diabetes Mellitus Tipo 2/genética , Jejum/metabolismo , Feminino , Predisposição Genética para Doença , Glucose/genética , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Relação Cintura-Quadril , Adulto Jovem
16.
Nat Commun ; 10(1): 2882, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253783

RESUMO

NLR Family CARD Domain Containing 5 (NLRC5), an important immune regulator in innate immunity, is involved in regulating inflammation and antigen presentation. However, the role of NLRC5 in vascular remodeling remains unknown. Here we report the role of NLRC5 on vascular remodeling and provide a better understanding of its underlying mechanism. Nlrc5 knockout (Nlrc5-/-) mice exhibit more severe intimal hyperplasia compared with wild-type mice after carotid ligation. Ex vivo data shows that NLRC5 deficiency leads to increased proliferation and migration of human aortic smooth muscle cells (HASMCs). NLRC5 binds to PPARγ and inhibits HASMC dedifferentiation. NACHT domain of NLRC5 is essential for the interaction with PPARγ and stimulation of PPARγ activity. Pioglitazone significantly rescues excessive intimal hyperplasia in Nlrc5-/- mice and attenuates the increased proliferation and dedifferentiation in NLRC5-deficient HASMCs. Our study demonstrates that NLRC5 regulates vascular remodeling by directly inhibiting SMC dysfunction via its interaction with PPARγ.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Túnica Íntima/metabolismo , Animais , Aorta , Apoptose , Pressão Sanguínea , Transplante de Medula Óssea , Proliferação de Células , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Frequência Cardíaca , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/metabolismo , Plasmídeos , Transcriptoma , Remodelação Vascular
17.
Diabetes Res Clin Pract ; 72(1): 88-92, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16288818

RESUMO

This purpose was to discuss optimal reference value for normal glucose tolerance (NGT) at different time points during an oral glucose tolerance test (OGTT) by receiver operating characteristic (ROC) analysis. One thousand seven hundred and forty-six subjects from March 2004 to March 2005 were given 75 g OGTT and the blood samples were collected at 0, 30, 60, 120 and 180 min for glucose measurement. Other demographic data (e.g. age, sex, body mass index, BMI) were also recorded. The status of NGT, impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and DM was determined according to American Diabetes Association (ADA) criteria. IGT and IFG were merged as impaired glucose regulation (IGR). Using IGR as the assumed test, the cutoff values at 0, 30, 60, 120 and 180 min during OGTT for normal reference range were calculated by ROC analysis. The cutoff values were 5.6, 9.5, 10.1, 7.8 and 6.1 mmol/l at 0, 30, 60, 120 and 180 min, respectively, in whole subjects. In addition, we provided the ROC information in age-stratified groups since there are differences among different age groups. When the results of OGTT were considered, the present study provided a reference range value to evaluate the status of glucose tolerance. Because of the heterogeneity of diabetes, further studies are necessity. And the sample collection is continuing.


Assuntos
Teste de Tolerância a Glucose/métodos , Idoso , Antropometria , Área Sob a Curva , Índice de Massa Corporal , Tamanho Corporal , China , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Curva ROC , Valores de Referência
18.
PLoS One ; 9(4): e94763, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24732788

RESUMO

Vaspin is a novel adipocytokine that has potential insulin-sensitizing effects. The aim of this study is to explore the role of vaspin in the progression of type 2 diabetes mellitus (T2DM) in humans through a longitudinal process. This was a 2-year follow-up study that included 132 patients with T2DM and 170 non-diabetic subjects. The serum vaspin and adiponectin levels were determined with ELISA. Anthropometric measurements, circulating glucose, hemoglobin A1c, insulin level, liver function, kidney function, and lipid profile were measured for each participant. The new onset of T2DM was counted in non-diabetic subjects and the glycemic control was analyzed in T2DM patients at follow-up. At enrollment, the serum vaspin and adiponectin levels were lower in T2DM patients compared with non-diabetic subjects. Significant positive correlation between serum vaspin and HDL-C levels (r = 0.23, P = 0.006) was observed in non-diabetic controls. The serum vaspin concentration was also significantly correlated with body mass index (BMI) (r = 0.19, P = 0.028), waist-hip ratio (WHR) (r = 0.17, P = 0.035) and homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.14, P = 0.029) in T2DM patients. In cohort analyses, it was found that lower serum vaspin [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.10-0.87, P = 0.015] and adiponectin (OR = 0.35, 95% CI: 0.20-0.72, P = 0.015) levels at baseline were risk factors for new onset of T2DM at follow-up. The percentage of insulin treatment in T2DM patients was higher in the sub-group with lower serum vaspin level than that in the sub-group with higher vaspin level at follow-up (55.3% vs. 44.7%, P = 0.020). Our study indicates that low serum concentration of vaspin is a risk factor for the progression of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Serpinas/sangue , Adiponectina/sangue , Idoso , Antropometria , Glicemia/análise , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/patologia , Progressão da Doença , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Glucose/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco
19.
J Diabetes Res ; 2014: 868732, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25133192

RESUMO

Vaspin and adiponectin are two adipocytokines with antidiabetic effects. Some studies reported that levels of adiponectin and vaspin were correlated with decreased glomerular filtration rate (FGR) and increased albuminuria. We therefore evaluated the vaspin and adiponectin levels in renal insufficiency (RI) patients with or without T2DM. Serum vaspin, adiponectin levels were measured in 416 subjects with or without T2DM. Analysis was made between groups divided by these subjects presence or absence of RI. We found that serum adiponectin level was significantly higher in nondiabetic patients with RI than in nondiabetic subjects without RI; however, there were no statistical differences between the diabetic patients with RI and without RI. In all the subjects, the serum adiponectin level was also higher in 50 individuals with RI than that in 366 subjects without RI. The serum vaspin levels showed no significant differences between the diabetic patients or nondiabetics subjects with RI and without RI. Contrary to adiponectin, the serum vaspin level was lower in 169 patients with T2DM than in 247 individuals without T2DM. Our data suggested that both of T2DM and renal insufficiency were correlated with the serum level of adiponectin. However, the serum vaspin levels showed no significant difference between the individuals with renal insufficiency and without renal insufficiency.


Assuntos
Adiponectina/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Rim/fisiopatologia , Insuficiência Renal/etiologia , Serpinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Insuficiência Renal/sangue , Insuficiência Renal/diagnóstico , Insuficiência Renal/fisiopatologia
20.
Exp Ther Med ; 6(2): 310-316, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24137180

RESUMO

Accumulating evidence has demonstrated that the Rho/Rho-associated protein kinase (Rho/ROCK) and nuclear factor κB (NF-κB) signaling pathways are involved in the pathogenesis of diabetic vascular injury. In this study, we investigated the beneficial effects of fasudil, a ROCK inhibitor, on vascular endothelial injury induced by advanced glycation end products (AGEs) in vitro. Human umbilical vein endothelial cells (HUVECs) were stimulated with AGEs and AGEs plus fasudil in various concentrations for different time periods. Monocyte-endothelial cell adhesion, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression, protein expression and activation of Rho/ROCK, activation of NF-κB and reactive oxygen species (ROS) production were evaluated. Fasudil suppressed AGE-induced monocyte-endothelial adhesion. Fasudil also reduced the mRNA and protein expression of VCAM-1 and MCP-1 in a concentration- and time-dependent manner. Moreover, increases in the protein levels of Rho/ROCK and ROCK activity mediated by AGEs were inhibited by the addition of fasudil. Additionally, fasudil attenuated AGE-induced NF-κB-dependent transcriptional activity and inhibition of NF-κB (IκB) phosphorylation. ROS production induced by AGEs was also reduced by fasudil in HUVECs. The results suggest that ROCK inhibition may protect the vascular endothelium against AGE-induced monocyte-endothelial adhesion in vitro through the reduction of ROS generation and the downregulation of NF-κB signaling. Thus, ROCK inhibition may be a novel therapeutic approach for the treatment of vascular complications in diabetes.

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